This study used a systems biology approach to predict the immunogenicity of the yellow fever vaccine (YF-17D) in humans. The researchers vaccinated 15 healthy individuals and collected blood samples at various time points to analyze immune responses. They found that YF-17D induced a network of antiviral genes, including those involved in interferon and innate antiviral responses, complement activation, and stress response pathways. The study identified gene signatures that correlated with the magnitude of CD8+ T cell and neutralizing antibody responses. Specifically, the signature *EIF2AK4* (GCN2) and *SLC2A6* (GLUT1) were key predictors of CD8+ T cell responses, while *TNFRSF17* (BLyS-BAFF receptor) was crucial for predicting antibody responses. These findings highlight the potential of systems biology approaches in predicting vaccine efficacy and could be applied to other vaccines to enhance their immunogenicity.This study used a systems biology approach to predict the immunogenicity of the yellow fever vaccine (YF-17D) in humans. The researchers vaccinated 15 healthy individuals and collected blood samples at various time points to analyze immune responses. They found that YF-17D induced a network of antiviral genes, including those involved in interferon and innate antiviral responses, complement activation, and stress response pathways. The study identified gene signatures that correlated with the magnitude of CD8+ T cell and neutralizing antibody responses. Specifically, the signature *EIF2AK4* (GCN2) and *SLC2A6* (GLUT1) were key predictors of CD8+ T cell responses, while *TNFRSF17* (BLyS-BAFF receptor) was crucial for predicting antibody responses. These findings highlight the potential of systems biology approaches in predicting vaccine efficacy and could be applied to other vaccines to enhance their immunogenicity.